| Background:Lung cancer is the first cancer no matter in incidence or death rates.lt is a major public health problem which inducing deaths from cancer in China and many other nations of the world. About more than 1.3 million new cases and over one million deaths of lung cancer worldwide every year. Estimated new lung cancer cases were 222,520 and about 157,300 people died of lung cancer-related diseases in America 2010.By 2025, China will become the biggest country of lung cancer as the incidence and mortality rising year by year. With the progress of medical and diagnostic technology, although the incidence of lung cancer reduced recent years, as in United States and other developed countries, the one-year, three-year, five-year survival rates did not improve obviously. Chemotherapy, surgery, radiation therapy are the main modalities for lung cancer. But due to the invasiveness and metastasis characteristics, most patients were found advanced. Even with radical resection, there are still 25% patients who appeared metastasis and recurrence in two years after operation, while the percentage of metastasis and recurrence for local treatment is higher. Median survival time for patients with advanced lung cancer just was 8-12 months,five-year survival rate was less than 20%, especially in China the 5-year survival rate was less than 10%, the small cell lung cancer is less than 5%, the distant metastases only as 1.7%. Invasion metastasis and recurrence are common biological characteristics of small cell lung cancer and non-small cell lung cancer, and they are also the major bottlenecks which affect the therapeutics and prognosis.With the progress of science and technology, people's knowledge are rising from appearance to molecular level in aspects of tumor occurrence, development and metastasis. But the development about the diagnosis and treatment of tumor recurrence and metastasis is so slow. As a result, to seek the predictor of lung cancer invasion,metastasis, judge prognosis, provide new target and prognosis indicators,individualized treatment, prolong life, is the direction and focus of lung cancer's research, as well as its emphasis and difficulty. Tumor invasion and metastasis exist in tumor cells, microenvironment and host cells, and they are complex processes of multiple genes, multiple steps, including tumor invasion, basement membrane degradation, matrix permeability, cell adhesion, and vessel formation.MMP-9 (matrix metalloproteinase-9) is a member of the matrix metalloproteinases family (matrix metalloproteinases, MMPs), and it can degradeⅣandⅤcollagen enzyme in ECM, rebuild the intercellular adhesion, and so on.Some researches also have found that MMPs also can promote the tumor blood vessels formation. CD 147, also called extracellular matrix metalloproteinases inducer(EMMPRIN), is a kind of transmembrane glycoprotein that was categorized as a member of the immunoglobulin superfamily (IgSF) of receptors, and is a new cell surface adherence molecules. CD 147 plays an important role in cancer, fetal, neuronal, lymphocyte and extracellular matrix development. It can precipitate tumor cell to secrete MMPs, and is highly expressed in breast cancer, liver cancer, and cervical cancer. However, very little is known about its function in lung cancer. COTL-1 (Coactosin-like protein-1) is one of the actin-binding protein, shares extremely high homology with coactosin. It can up regulate 5LO, interacts with 5LO and actin via different binding sites, participate in cytoskeleton movements, regulate the inflammatory response, such as the chemotaxis and phagocytosis of leucocytes. It is reported high expression in bladder cancer, pancreatic cancer, and small cell lung cancer. But the reports are so little, and its role in tumor is deserved to research.In addition, tumor growth, invasion, metastasis are closely related to the neovascularization, and MVD (microvessel density) has been considered to be the ideal indicators on the situation of tumor angiogenesis. Tumor cells through the basement membrane, extracellular matrix, tumor proliferation and angiogenesis are the basic processes of tumor invasion and metastasis, whether MMP-9, CD 147 and COTL-1 involved in lung cancer invasion and metastasis is worth to study. But there are so little research on the relationship between COTL-1 and lung cancer, and the research concerning the correlation between MMP-9,CD 147 and lung cancer has been carried on, mainly on the clinicopathological significance. And it was litter reported on the relationships about MMP-9,CD147,COTL-1 with lung cancer development and metastatic mechanism, also was litter reported on the interrelationship among them.Objective:To investigate the expression levers of MMP-9, CD147 and COTL-1 in lung cancer primary tumors, adjacent non-tumor lung tissues and metastatic lymph nodes, the clinicopathological significance of MMP-9, CD147and COTL-1 in lung cancer primary tumors and the relationship between MMP-9,CD147,COTL-1 and lung cancer lymph node metastasis, microvascular formation and other relevant clinical pathological factors.By analyzing its role in lung cancer occurs, transfer, and prognosis, to provide theoretical basis for clinical diagnosis, individualized treatment and forecast prognosis about lung cancer. Methods:1. In the study, immunohistochemical (IHC) staining was utilized for determing MMP-9, CD147, COTL-1, and CD34-MVD in lung cancer primary tumors, adjacent normal tissue and metastatic lymph nodes in the expression.(1) Compare the differences of the expression levels of MMP-9, CD147and COTL-1 in 47 non-small cell lung cancer primary tumors,18 small cell lung cancer primary tumors and 27 adjacent non-tumor lung tissues.(2) Analysis the correlations between MMP-9, CD 147, COTL-1 expression in 65 lung cancer primary tumors and clinical pathological factors (including gender, age, clinical stage, pathological type, tumor size, differentiation, lymph nodes metastases, lifetime)(3) Analysis the correlations between MMP-9, CD 147, COTL-1 expression and CD34-MVD in 65 lung cancer primary tumors, and lymph nodes metastases.(4) Analysis the correlations between MMP-9expression, CD 147 expression and COTL-1 expression one another.2. Statistical methods:All statistical analyses were performed using SPSS13.0 software. The differences of MMP-9, CD147and COTL-1 expression rate between primary tumors and adjacent non-tumor lung tissues were analyzed by Chi-square test. The relationships of the expression of MMP-9, CD147and COTL-1 protein of lung cancer patients with their clinical-pathologic features were analyzed using Chi-square test or Kruska-Wallis test. The differences of CD34-MVD values between MMP-9, CD 147, COTL-1 diffrent expression were analyzed by independent-samples t test. The Spearman correlation analysis was used to analyze the relationships among MMP-9 expression and CD147 expression and COTL-1 expression. Kaplan-Meier method was used to analyze the relationship of MMP-9, CD147and COTL-1 protein expression with lung cancer patients' survival time retrospectively.Differences were considered as significant when the P value was less than 0.05. Results:1. The MMP-9 protein positive expression rate were 65.96%,66.67% and 11.11% in 47 cases with non-small cell lung cancer patients,18 cases with small cell lung cancer and 27 cases adjacent non-tumor lung tissue respectively. The CD147 protein positive expression rate were 72.34%,66.67% and 3.70% in non-small cell lung cancer patients, small cell lung cancer and adjacent non-tumor lung tissue respectively. COTL-1 expression rate were 68.09%,72.22% and 14.81% in corresponding domains.Compared with adjacent non-tumor lung tissues, MMP-9, CD147 and COTL-1 expressions in primary lung cancer, were significantly enhanced (P<0.05).2. MMP-9 protein expression in primary tumors correlated closely with tumor size, clinical staging and lymph node metastasis (P value:0.009,0.017,0.029), while not correlated with gender, age, histological type and differentiation (P value:0.232, 0.656,0.951,0.280). The median survival time of lung cancer patients who were detected positive-expression MMP-9 protein was 17.0 months, significantly lower than the patients with negative-expression MMP-9 protein (x2=13.197, P<0.05).3. CD 147 protein expression in primary tumors correlated closely with tumor size, clinical staging and lymph node metastasis (P value:0.000,0.001,0.024), while not correlated with gender, age, histological type and differentiation (P value:0.690, 0.222,0.763,0.962). The median survival time of lung cancer patients who were detected positive-expression CD 147 protein was 17.0 months, significantly lower than the patients with negative-expression CD 147 protein (χ2=10.676, P=0.001).4. COTL-1 protein expression in primary tumors correlated closely with differentiation (P=0.035), while not correlated with gender, age, tumor size, histological type, clinical staging and lymph node metastasis (P value:0.377,0.507, 0.438,0.808,0.414,0.145). The median survival time of lung cancer patients who were detected positive-expression COTL-1 protein was 22.0 months, lower than the patients with negative-expression COTL-1 protein, but the difference was not significant (χ2=2.297,P=0.130>0.05). The median survival time of lung cancer patients who were detected positive-expression MMP-9,CD 147 and COTL-1 was 14.0 months, significantly lower than the patients with negative-expression anyone of MMP-9,CD147,COTL-1 protein (χ2=14.966, P=0.001).5. CD34-MVD were 29±12.785/mm2,26.928±13.833/mm2 and 8.604±5.370/mm2 in lung cancer primary tumors, adjacent non-tumor lung tissues and lymph node metastases respectively, there was statistical significance among them (F=34.859, P<0.001).6. In lung cancer primary tumors-the differences of CD34-MVD values between positive-expression MMP-9/CD147/COTL-1 cases and negative-expression MMP-9/CD147/COTL-1 cases were significant (P<0.05). In lymph node metastases, the difference of CD34-MVD values between positive-expression MMP-9 cases and negative-expression MMP-9 cases was significant (P<0.05), while the differnces of CD34-MVD values between positive-expression CD147/COTL-1 cases and negative-expression CD147/COTL-1 cases were no significant (P=0.066/0.240)7. The expression intensity of MMP-9 and CD 147 was correlated closely (r=0.674); the expression intensity of MMP-9 and COTL-1 was statistical significance, but not correlated closely (r=0.467); the expression intensity of CD147 and COTL-1 was correlated closely (r=0.556)Conclusions:1. MMP-9/CD147/COTL-1 expression were positively associated with CD34-MVD, MMP-9/CD147 expression were positively associated with lymph node metastasis, suggesting that MMP-9/CD147/COTL-1 may stimulate angiogenic factor receptor tyrosine kinase activity.2. MMP-9/CD147 expression correlated closely with lymph node metastasis and prognosis, COTL-1 had related trend with prognosis, suggesting that, MMP-9/CD147/COTL-1 may participate in the development, progress and metastasis of lung cancer, they may be promising targets for lung cancer treatment.3. MMP-9, CD 147 and COTL-1 expression were correlated closely each other in lung cancer. They may have a synergistic effect on lung cancer development, progress and metastasis by some way, and it provides more choices for targeted therapy of lung cancer. |
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